Hepatitis C virus (HCV) has infected more than 180 million people worldwide. It is estimated that three to four million persons are newly infected each year, 70% of whom will develop chronic hepatitis. HCV is responsible for 50-76% of all liver cancer cases, and two thirds of all liver transplants in the developed world. Standard therapy (pegylated interferon alpha plus ribavirin) is only effective in 50-60% of patients; however, its effectiveness is not well understood and it is associated with significant side-effects. Therefore, there is an urgent need for new drugs to treat and/or cure HCV (1: Chen K X, Njoroge F G. A review of HCV protease inhibitors. Curr Opin Investig Drugs. 2009 8, 821-37; 2: Garg G, Kar P. Management of HCV infection: current issues and future options. Trop Gastroenterol. 2009 30, 11-8; 3: Pereira A A, Jacobson I M. New and experimental therapies for HCV. Nat Rev Gastroenterol Hepatol. 2009 7, 403-11).
The HCV genome comprises a positive-strand RNA enclosed in a nucleocapsid and lipid envelope and consists of 9.6 kb ribonucleotides, which encodes a large polypeptide of about 3000 amino acids (Dymock et al. Antiviral Chemistry & Chemotherapy 2000, 11, 79). Following maturation, this polypeptide is cut into at least 10 proteins. The NS3 serine protease, located in the N-terminal domain of the NS3 protein, mediates all of the subsequent cleavage events downstream in the polyprotein. Because of its role, the NS3 serine protease is an ideal drug target and previous research has shown hexapeptides as well as tripeptides show varying degrees of inhibition, as discussed in U.S. patent applications US2005/0020503, US2004/0229818, and US2004/00229776. Macrocyclic compounds that exhibit anti-HCV activity have also been disclosed in International patent applications nos. WO20061119061, WO2007/015855 and WO2007/016441 (all Merck & Co., Inc.).
The discovery of novel antiviral strategies to selectively inhibit HCV replication has long been hindered by the lack of convenient cell culture models for the propagation of HCV. This hurdle has been overcome first with the establishment of the HCV replicon system in 1999 (Bartenschlager, R., Nat. Rev. Drug Discov. 2002, 1, 911-916 and Bartenschlager, R., J. Hepatol. 2005, 43, 210-216) and, in 2005, with the development of robust HCV cell culture models (Wakita, T., et al., Nat. Med. 2005, 11, 791-6; Zhong, J., et al., Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 9294-9; Lindenbach, B. D., et al., Science 2005, 309, 623-6).
It would be advantageous to provide new antiviral or chemotherapy agents, compositions including these agents, and methods of treatment using these agents, particularly to treat drug resistant or mutant viruses. The present invention provides such agents, compositions and methods.